tbuckley/cabot-search huggingface dataset:
Association Between Hemorrhage Control Interventions and Mortality in US Trauma Patients With Hemodynamically Unstable Pelvic Fractures
Authors: Tanya Anand, Khaled El-Qawaqzeh, Adam Nelson, Hamidreza Hosseinpour, Michael Ditillo, Lynn Gries, Lourdes Castanon, Bellal Joseph
Journal: JAMA Surgery (2022)

Management of hemodynamically unstable pelvic fractures remains a challenge. Hemostatic interventions are used alone or in combination. There is a paucity of data on the association between the pattern of hemorrhage control interventions and outcomes after a severe pelvic fracture.To characterize clinical outcomes and study the patterns of hemorrhage control interventions in hemodynamically unstable pelvic fractures.In this cohort study, a retrospective review was performed of data from the 2017 American College of Surgeons Trauma Quality Improvement Program database, a national multi-institutional database of trauma patients in the United States. Adult patients (aged ≥18 years) with pelvic fractures who received early transfusions (≥4 units of packed red blood cells in 4 hours) and underwent intervention for pelvic hemorrhage control were identified. Use and order of preperitoneal pelvic packing (PP), pelvic angioembolization (AE), and resuscitative endovascular balloon occlusion of the aorta (REBOA) in zone 3 were examined and compared against the primary outcome of mortality. The associations between intervention patterns and mortality, complications, and 24-hour transfusions were further examined by backward stepwise regression analyses. Data analyses were performed in September 2021.Primary outcomes were rates of 24-hour, emergency department, and in-hospital mortality. Secondary outcomes were major in-hospital complications.A total of 1396 patients were identified. Mean (SD) age was 47 (19) years, 975 (70%) were male, and the mean (SD) lowest systolic blood pressure was 71 (25) mm Hg. The median (IQR) Injury Severity Score was 24 (14-34), with a 24-hour mortality of 217 patients (15.5%), ED mortality of 10 patients (0.7%), in-hospital mortality of 501 patients (36%), and complication rate of 574 patients (41%). Pelvic AE was the most used intervention (774 [55%]), followed by preperitoneal PP (659 [47%]) and REBOA zone 3 (126 [9%]). Among the cohort, 1236 patients (89%) had 1 intervention, 157 (11%) had 2 interventions, and 3 (0.2%) had 3 interventions. On regression analyses, only pelvic AE was associated with a mortality reduction (odds ratio [OR], 0.62; 95% CI, 0.47 to 0.82; P < .001). Preperitoneal PP was associated with increased odds of complications (OR, 1.39; 95% CI, 1.07 to 1.80; P = .01). Increasing number of interventions was associated with increased 24-hour transfusions (β = +5.4; 95% CI, +3.5 to +7.5; P < .001) and mortality (OR, 1.57; 95% CI, 1.05 to 2.37; P = .03), but not with complications.This study found that among patients with pelvic fracture who received early transfusions and at least 1 invasive pelvic hemorrhage control intervention, more than 1 in 3 died, despite the availability of advanced hemorrhage control interventions. Only pelvic AE was associated with a reduction in mortality.
Tocilizumab for Corticosteroid-Refractory Immune Checkpoint Inhibitor–Induced Generalized Morphea
Authors: Manon Blaise, Nathalie Cardot-Leccia, Barbara Seitz-Polski, Alexandra Picard-Gauci, Clémence Bertold, Thierry Passeron, Henri Montaudié
Journal: JAMA Dermatology (2022)

This case report describes a 78-year old woman with a stage IIA BRAF wild-type melanoma on the left leg who experienced a grade 2 vitiligo, a marked skin thickening, and painful swelling of the limbs.
CCT251545 enhances drug delivery and potentiates chemotherapy in multidrug-resistant cancers by Rac1-mediated macropinocytosis
Authors: Siyuan Qin, Zhe Zhang, Zhao Huang, Yinheng Luo, Ningna Weng, Bowen Li, Yongquan Tang, Li Zhou, Jingwen Jiang, Yi Lu, Jichun Shao, Na Xie, Edouard C. Nice, Zhe-Sheng Chen, Jian Zhang, Canhua Huang
Journal: Drug Resistance Updates (2022)
A Case of Right Bundle Branch Block With Changing Axis
Authors: Robert B. King, Ramil Goel
Journal: JAMA Cardiology (2022)

A man in his 80s presented with recurrent presyncope and bradycardia. An electrocardiogram showed atrial fibrillation with an irregular ventricular rate of around 60 beats per minute, right bundle branch block, and left posterior fascicular block. What would you do next?
Prothrombin Complex Concentrate and Cardiac Surgery
Authors: Nirvik Pal, Mark Nelson
Journal: JAMA Surgery (2022)

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Clinical Trial Design Challenges and Opportunities for Emerging Treatments for Opioid Use Disorder
Authors: Brian D. Kiluk, Bethea A. Kleykamp, Sandra D. Comer, Roland R. Griffiths, Andrew S. Huhn, Matthew W. Johnson, Kyle M. Kampman, Marco Pravetoni, Kenzie L. Preston, Ryan Vandrey, Cecilia L. Bergeria, Michael P. Bogenschutz, Randall T. Brown, Kelly E. Dunn, Robert H. Dworkin, Patrick H. Finan, Peter S. Hendricks, Elisabeth J. Houtsmuller, Thomas R. Kosten, Dustin C. Lee, Frances R. Levin, Aimee McRae-Clark, Charles L. Raison, Kurt Rasmussen, Dennis C. Turk, Roger D. Weiss, Eric C. Strain
Journal: JAMA Psychiatry (2022)

Importance Novel treatments for opioid use disorder (OUD) are needed to address both the ongoing opioid epidemic and long-standing barriers to existing OUD treatments that target the endogenous μ-opioid receptor (MOR) system. The goal of this review is to highlight unique clinical trial design considerations for the study of emerging treatments for OUD that address targets beyond the MOR system. In November 2019, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration sponsored a meeting to discuss the current evidence regarding potential treatments for OUD, including cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics, such as vaccines. Observations Consensus recommendations are presented regarding the most critical elements of trial design for the evaluation of novel OUD treatments, such as: (1) stage of treatment that will be targeted (eg, seeking treatment, early abstinence/detoxification, long-term recovery); (2) role of treatment (adjunctive with or independent of existing OUD treatments); (3) primary outcomes informed by patient preferences that assess opioid use (including changes in patterns of use), treatment retention, and/or global functioning and quality of life; and (4) adverse events, including the potential for opioid-related relapse or overdose, especially if the patient is not simultaneously taking maintenance MOR agonist or antagonist medications. Conclusions and Relevance Applying the recommendations provided here as well as considering input from people with lived experience in the design phase will accelerate the development, translation, and uptake of effective and safe therapeutics for individuals struggling with OUD.
Do Clinicians Have a Duty to Participate in Pragmatic Clinical Trials?
Authors: Andrew Garland, Stephanie Morain, Jeremy Sugarman
Journal: The American Journal of Bioethics (2022)

Clinicians have good moral and professional reasons to contribute to pragmatic clinical trials (PCTs). We argue that clinicians have a defeasible duty to participate in this research that takes place in usual care settings and does not involve substantive deviation from their ordinary care practices. However, a variety of countervailing reasons may excuse clinicians from this duty in particular cases. Yet because there is a moral default in favor of participating, clinicians who wish to opt out of this research must justify their refusal. Reasons to refuse include that the trial is badly designed in some way, that the trial activities will violate the clinician's conscience, or that the trial will impose excessive burdens on the clinician.
Targeting the central nervous system in lysosomal storage diseases: Strategies to deliver therapeutics across the blood-brain barrier
Authors: Bethan J. Critchley, H. Bobby Gaspar, Sara Benedetti
Journal: Molecular Therapy (2022)

Lysosomal storage diseases (LSDs) are multisystem inherited metabolic disorders caused by dysfunctional lysosomal activity, resulting in the accumulation of undegraded macromolecules in a variety of organs/tissues, including the central nervous system (CNS). Treatments include enzyme replacement therapy, stem/progenitor cell transplantation, and in vivo gene therapy. However, these treatments are not fully effective in treating the CNS as neither enzymes, stem cells, nor viral vectors efficiently cross the blood-brain barrier. Here, we review the latest advancements in improving delivery of different therapeutic agents to the CNS and comment upon outstanding questions in the field of neurological LSDs.
Engineering of efficiency-enhanced Cas9 and base editors with improved gene therapy efficacies
Authors: Shuming Yin, Mei Zhang, Yang Liu, Xiaoyue Sun, Yuting Guan, Xi Chen, Lei Yang, Yanan Huo, Jing Yang, Xiaohui Zhang, Honghui Han, Jiqin Zhang, Min-Min Xiao, Mingyao Liu, Jiazhi Hu, Liren Wang, Dali Li
Journal: Molecular Therapy (2022)

Editing efficiency is pivotal for the efficacies of CRISPR-based gene therapies. We found that fusing an HMG-D domain to the N terminus of SpCas9 (named efficiency-enhanced Cas9 [eeCas9]) significantly increased editing efficiency by 1.4-fold on average. The HMG-D domain also enhanced the activities of non-NGG PAM Cas9 variants, high-fidelity Cas9 variants, smaller Cas9 orthologs, Cas9-based epigenetic regulators, and base editors in cell lines. Furthermore, we discovered that eeCas9 exhibits comparable off-targeting effects with Cas9, and its specificity could be increased through ribonucleoprotein delivery or using hairpin single-guide RNAs and high-fidelity Cas9s. The entire eeCas9 could be packaged into an adeno-associated virus vector and exhibited a 1.7- to 2.6-fold increase in editing efficiency targeting the Pcsk9 gene in mice, leading to a greater reduction of serum cholesterol levels. Moreover, the efficiency of eeA3A-BE3 also surpasses that of A3A-BE3 in targeting the promoter region of γ-globin genes or BCL11A enhancer in human hematopoietic stem cells to reactivate γ-globin expression for the treatment of β-hemoglobinopathy. Together, eeCas9 and its derivatives are promising editing tools that exhibit higher activity and therapeutic efficacy for both in vivo and ex vivo therapeutics.
Research progress of therapeutic effects and drug resistance of immunotherapy based on PD-1/PD-L1 blockade
Authors: Kun Pang, Zhen-Duo Shi, Liu-Ya Wei, Yang Dong, Yu-Yang Ma, Wei Wang, Guang-Yue Wang, Ming-Yang Cao, Jia-Jun Dong, Yu-Ang Chen, Peng Zhang, Lin Hao, Hao Xu, Deng Pan, Zhe-Sheng Chen, Cong-Hui Han
Journal: Drug Resistance Updates (2022)
For insights into the real world, consider real-world data
Authors: Sana Raoof, Razelle Kurzrock
Journal: Science Translational Medicine (2022)

Randomized control trials (RCTs) are required before drug and device approvals and have contributed to patient safety, but they have also increased the cost and time of regulatory assessments. We propose that using real-world evidence to complement or, in some settings, to replace RCTs will accelerate delivery of new drugs to patients.
Single-Cell Analysis in Lung Adenocarcinoma Implicates RNA Editing in Cancer Innate Immunity and Patient Prognosis
Authors: Tracey W. Chan, Jack P. Dodson, Jaron Arbet, Paul C. Boutros, Xinshu Xiao
Journal: Cancer Research (2022)

Abstract RNA editing modifies single nucleotides of RNAs, regulating primary protein structure and protein abundance. In recent years, the diversity of proteins and complexity of gene regulation associated with RNA editing dysregulation has been increasingly appreciated in oncology. Large-scale shifts in editing have been observed in bulk tumors across various cancer types. However, RNA editing in single cells and individual cell types within tumors has not been explored. By profiling editing in single cells from lung adenocarcinoma biopsies, we found that the increased editing trend of bulk lung tumors was unique to cancer cells. Elevated editing levels were observed in cancer cells resistant to targeted therapy, and editing sites associated with drug response were enriched. Consistent with the regulation of antiviral pathways by RNA editing, higher editing levels in cancer cells were associated with reduced antitumor innate immune response, especially levels of natural killer cell infiltration. In addition, the level of RNA editing in cancer cells was positively associated with somatic point mutation burden. This observation motivated the definition of a new metric, RNA editing load, reflecting the amount of RNA mutations created by RNA editing. Importantly, in lung cancer, RNA editing load was a stronger predictor of patient survival than DNA mutations. This study provides the first single cell dissection of editing in cancer and highlights the significance of RNA editing load in cancer prognosis. Significance: RNA editing analysis in single lung adenocarcinoma cells uncovers RNA mutations that correlate with tumor mutation burden and cancer innate immunity and reveals the amount of RNA mutations that strongly predicts patient survival. See related commentary by Luo and Liang, p. 351
Recombinant vesicular stomatitis virus–vectored vaccine induces long-lasting immunity against Nipah virus disease
Authors: Courtney Woolsey, Viktoriya Borisevich, Alyssa C. Fears, Krystle N. Agans, Daniel J. Deer, Abhishek N. Prasad, Rachel O’Toole, Stephanie L. Foster, Natalie S. Dobias, Joan B. Geisbert, Karla A. Fenton, Robert W. Cross, Thomas W. Geisbert
Journal: Journal of Clinical Investigation (2022)

The emergence of the novel henipavirus, Langya virus, received global attention after the virus sickened over three dozen people in China. There is heightened concern that henipaviruses, as respiratory pathogens, could spark another pandemic, most notably the deadly Nipah virus (NiV). NiV causes near-annual outbreaks in Bangladesh and India and induces a highly fatal respiratory disease and encephalitis in humans. No licensed countermeasures against this pathogen exist. An ideal NiV vaccine would confer both fast-acting and long-lived protection. Recently, we reported the generation of a recombinant vesicular stomatitis virus–based (rVSV-based) vaccine expressing the NiV glycoprotein (rVSV-ΔG-NiVBG) that protected 100% of nonhuman primates from NiV-associated lethality within a week. Here, to evaluate the durability of rVSV-ΔG-NiVBG, we vaccinated African green monkeys (AGMs) one year before challenge with an uniformly lethal dose of NiV. The rVSV-ΔG-NiVBG vaccine induced stable and robust humoral responses, whereas cellular responses were modest. All immunized AGMs (whether receiving a single dose or prime-boosted) survived with no detectable clinical signs or NiV replication. Transcriptomic analyses indicated that adaptive immune signatures correlated with vaccine-mediated protection. While vaccines for certain respiratory infections (e.g., COVID-19) have yet to provide durable protection, our results suggest that rVSV-ΔG-NiVBG elicits long-lasting immunity.
Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression
Authors: Sean H. Colligan, Andrea M. Amitrano, Robert A. Zollo, Jennifer Peresie, Elliot D. Kramer, Brian Morreale, Joseph Barbi, Prashant K. Singh, Han Yu, Jianmin Wang, Mateusz Opyrchal, David B. Sykes, Michael J. Nemeth, Scott I. Abrams
Journal: Journal of Clinical Investigation (2022)

While immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape in oncology, they are effective in select subsets of patients. Efficacy may be limited by tumor-driven immune suppression, of which 1 key mechanism is the development of myeloid-derived suppressor cells (MDSCs). A fundamental gap in MDSC therapeutics is the lack of approaches that target MDSC biogenesis. We hypothesized that targeting MDSC biogenesis would mitigate MDSC burden and bolster tumor responses to ICIs. We tested a class of agents, dihydroorotate dehydrogenase (DHODH) inhibitors, that have been previously shown to restore the terminal differentiation of leukemic myeloid progenitors. DHODH inhibitors have demonstrated preclinical safety and are under clinical study for hematologic malignancies. Using mouse models of mammary cancer that elicit robust MDSC responses, we demonstrated that the DHODH inhibitor brequinar (a) suppressed MDSC production from early-stage myeloid progenitors, which was accompanied by enhanced myeloid maturation; (b) augmented the antitumor and antimetastatic activities of programmed cell death 1–based (PD-1–based) ICI therapy in ICI-resistant mammary cancer models; and (c) acted in concert with PD-1 blockade through modulation of MDSC and CD8+ T cell responses. Moreover, brequinar facilitated myeloid maturation and inhibited immune-suppressive features in human bone marrow culture systems. These findings advance the concept of MDSC differentiation therapy in immuno-oncology.
Decoupling dedifferentiation and G2/M arrest in kidney fibrosis
Authors: Benjamin D. Humphreys
Journal: Journal of Clinical Investigation (2022)

Understanding the cellular mechanisms underlying chronic kidney disease (CKD) progression is required to develop effective therapeutic approaches. In this issue of the JCI, Taguchi, Elias, et al. explore the relationship between cyclin G1 (CG1), an atypical cyclin that induces G2/M proximal tubule cell cycle arrest, and epithelial dedifferentiation during fibrogenesis. While CG1-knockout mice were protected from fibrosis and had reduced G2/M arrest, protection was unexpectedly independent of induction of G2/M arrest. Rather, CG1 drove fibrosis by regulating maladaptive dedifferentiation in a CDK5-dependent mechanism. These findings highlight the importance of maladaptive epithelial dedifferentiation in kidney fibrogenesis and identify CG1/CDK5 signaling as a therapeutic target in CKD progression.
Bring on the brequinar: an approach to enforce the differentiation of myeloid-derived suppressor cells
Authors: Natalie K. Horvat, Gregory B. Lesinski
Journal: Journal of Clinical Investigation (2022)

Myeloid-derived suppressor cells (MDSCs) hinder antitumor immunity in multiple cancer types. While brequinar (BRQ), an inhibitor of dihydroorotate dehydrogenase, shows cytotoxicity in hematological malignancy, it has not yet been adapted to attenuate MDSCs by augmenting bone marrow progenitors in breast cancer. In this issue of the JCI, Colligan et al. demonstrate that BRQ restored terminal differentiation of MDSCs. Using in vivo models of immunotherapy-resistant breast cancer, the authors uncovered a mechanism by which BRQ promoted myeloid cell differentiation by limiting their suppressive function and enhancing the efficacy of immune checkpoint blockade therapy. The findings offer insight into the biogenesis of MDSCs, provide an alternative avenue for cancers that remain unresponsive to conventional therapies, and may be extended to future translational studies in patients.
Doris Duke Charitable Foundation Fund to Retain Clinical Scientists: innovating support for early-career family caregivers
Authors: Reshma Jagsi, T. DeLene Beeland, Kevin Sia, Lauren A. Szczygiel, Matthew R. Allen, Vineet M. Arora, Megan Bair-Merritt, Melissa D. Bauman, Hillary R. Bogner, Gail Daumit, Esa Davis, Angela Fagerlin, Daniel E. Ford, Rasheed Gbadegesin, Kathy Griendling, Katherine Hartmann, S. Susan Hedayati, Rebecca D. Jackson, Susan Matulevicius, Michael J. Mugavero, Eric J. Nehl, Tuhina Neogi, Judith G. Regensteiner, Michael A. Rubin, Doris Rubio, Kanakadurga Singer, Brownsyne Tucker Edmonds, Anna Volerman, Sandra Laney, Carrie Patton, Sindy Escobar Alvarez
Journal: Journal of Clinical Investigation (2022)
Cyclin G1 induces maladaptive proximal tubule cell dedifferentiation and renal fibrosis through CDK5 activation
Authors: Kensei Taguchi, Bertha C. Elias, Sho Sugahara, Snehal Sant, Benjamin S. Freedman, Sushrut S. Waikar, Ambra Pozzi, Roy Zent, Raymond C. Harris, Samir M. Parikh, Craig R. Brooks
Journal: Journal of Clinical Investigation (2022)

Acute kidney injury (AKI) occurs in approximately 13% of hospitalized patients and predisposes patients to chronic kidney disease (CKD) through the AKI-to-CKD transition. Studies from our laboratory and others have demonstrated that maladaptive repair of proximal tubule cells (PTCs), including induction of dedifferentiation, G2/M cell cycle arrest, senescence, and profibrotic cytokine secretion, is a key process promoting AKI-to-CKD transition, kidney fibrosis, and CKD progression. The molecular mechanisms governing maladaptive repair and the relative contribution of dedifferentiation, G2/M arrest, and senescence to CKD remain to be resolved. We identified cyclin G1 (CG1) as a factor upregulated in chronically injured and maladaptively repaired PTCs. We demonstrated that global deletion of CG1 inhibits G2/M arrest and fibrosis. Pharmacological induction of G2/M arrest in CG1-knockout mice, however, did not fully reverse the antifibrotic phenotype. Knockout of CG1 did not alter dedifferentiation and proliferation in the adaptive repair response following AKI. Instead, CG1 specifically promoted the prolonged dedifferentiation of kidney tubule epithelial cells observed in CKD. Mechanistically, CG1 promotes dedifferentiation through activation of cyclin-dependent kinase 5 (CDK5). Deletion of CDK5 in kidney tubule cells did not prevent G2/M arrest but did inhibit dedifferentiation and fibrosis. Thus, CG1 and CDK5 represent a unique pathway that regulates maladaptive, but not adaptive, dedifferentiation, suggesting they could be therapeutic targets for CKD.
Not young but still immature: a HIF-1α–mediated maturation checkpoint in regenerating muscle
Authors: Rahagir Salekeen, Michael Kyba
Journal: Journal of Clinical Investigation (2022)

Muscle fibers express particular isoforms of contractile proteins, depending on the fiber’s function and the organism’s developmental stage. In the adult, after a muscle injury, newly generated fibers transition through embryonic and neonatal myosins, prior to selecting their distinctive adult myosin isoform. In this issue of the JCI, Wang et al. discover a checkpoint that regulates the neonatal-to-adult myosin isoform transition. They found that HIF-1α regulated this checkpoint, with elevated HIF-1α levels blocking progression, while HIF-1α knockout accelerated the transition. They further related these findings to centronuclear myopathy, a disease in which HIF-1α is similarly elevated and neonatal myosin expression is maintained. These findings highlight a maturation checkpoint that impacts the skeletal muscle regeneration following ischemic injury, providing a pharmacologically accessible pathway in injury and diseases such as centronuclear myopathy.